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The Journal of Lipid Research, Vol. 40, 318-327, February 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

The apolipoprotein B R3531C mutation: characteristics of 24 subjects from 9 kindreds

Familial ligand-defective apolipoprotein B (apoB) is a group of disorders caused by mutations in the apoB gene. In this report the R3531C mutation is characterized further using a monoclonal antibody MB19/dynamic laser light scattering technique to measure ratios of Cys³⁵³¹ to normal low density lipoprotein (LDL) particles. All six subjects studied showed a preferential accumulation of particles carrying the defective apoB allotype. We determined binding properties of LDL from R3531C heterozygotes by measurement of high-affinity binding to LDL receptors on fibroblasts and its ability promote growth of U937 cells. LDL from R3531C heterozygotes, compared to normal LDL, had 49.3% of the binding affinity and was 74% as effective in a U937 cell proliferation assay. To identify new probands, we screened 2570 subjects for the R3531C mutation. Nine probands were found with 15 affected relatives. Of the seven haplotypes we uncovered, two were novel, while five were identical to one initially reported as associated with Cys³⁵³¹. Three silent mutations were detected also: T3540T, N3542N and T3552T. Analysis of lipid profiles of R3531C families showed, as with the R3500Q mutation, variable expression of the phenotype, modulated by environmental and other genetic factors. Both mutations tend to produce lower plasma levels of LDL in affected subjects than do defects of the LDL receptor (familial hypercholesterolemia, FH).

This study shows that the Cys³⁵³¹ LDL particles are not only defective at binding to the LDL receptor, as determined by two separate methods, but that in all cases they accumulate preferentially compared to the normal allotype.—Pullinger, C. R., D. Gaffney, M. M. Gutierrez, M. J. Malloy, V. N. Schumaker, C. J. Packard, and J. P. Kane. Apolipoprotein B R3531C mutation: characteristics of 24 subjects from 9 kindreds. J. Lipid Res. 1999. 40: 318–327.

Supplementary key words: apolipoprotein B, atherosclerosis, hypercholesterolemia, haplotypes, genetic mutation

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